ENTINOSTAT

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C21H20N4O3
Molecular Weight	376.4085
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

NC1=CC=CC=C1NC(=O)C2=CC=C(CNC(=O)OCC3=CN=CC=C3)C=C2

InChI

InChIKey=INVTYAOGFAGBOE-UHFFFAOYSA-N

InChI=1S/C21H20N4O3/c22-18-5-1-2-6-19(18)25-20(26)17-9-7-15(8-10-17)13-24-21(27)28-14-16-4-3-11-23-12-16/h1-12H,13-14,22H2,(H,24,27)(H,25,26)

HIDE SMILES / InChI

Molecular Formula	C21H20N4O3
Molecular Weight	376.4085
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: http://adisinsight.springer.com/drugs/800012663
Curator's Comment: Description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/17383217 https://www.ncbi.nlm.nih.gov/pubmed/21888556 https://www.ncbi.nlm.nih.gov/pubmed/12975486

Entinostat (MS-275) is an orally active, highly selective, small-molecule histone deacetylase inhibitor (HDACi) derived from benzamide. Entinostat preferentially inhibited HDAC1 versus HDAC3 and had no inhibitory activity toward HDAC8. The time to maximum plasma concentration (tmax) of entinostat ranged from 0.5 to 60h (median of 2h). Elimination of the drug was bi-exponential, with a terminal half-life of 30-80h. Entinostat is a well-tolerated that demonstrates promising therapeutic potential in both solid and hematologic malignancies. Its efficacy does not appear directly dose-related, and as such, more relevant biomarkers are needed to adequately assess its activity.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Histone deacetylase 1 51 Target ID: CHEMBL325 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12975486	Inhibitor 8228		0.3 µM [IC50]
Histone deacetylase 3 35 Target ID: CHEMBL1829 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12975486	Inhibitor 8228		8.0 µM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Breast cancer 431 Sources: http://adisinsight.springer.com/drugs/800012663	Primary	Phase III 663	Unknown Approved Use Unknown
Non-small cell lung cancer 201 Sources: http://adisinsight.springer.com/drugs/800012663	Primary	Phase II 1144	Unknown Approved Use Unknown
Acute myeloid leukemia 135 Sources: http://adisinsight.springer.com/drugs/800012663	Primary	Phase II 1144	Unknown Approved Use Unknown

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
inhibitor 1579			inhibitor 1599

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
P-gp 1437 CYPs 22	OATP1B3 347 UGTs 13 OATP1B1 403 CYPs 33	BCRP 75 CYP19 1

Drug as perpetrator

Target	Modality	Activity
BCRP 765	inducer 1542 Sources: https://pubmed.ncbi.nlm.nih.gov/26133921/	no
CYP3A4 1909	inhibitor 3240 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/609494#sid=103197084	yes [IC50 0.73 uM]
P-gp 1626	inhibitor 3240 Sources: https://pubchem.ncbi.nlm.nih.gov/bioassay/1346987#sid=363676644	yes [IC50 9.2 uM]
CYP19 2	inducer 1542 Sources: https://pubmed.ncbi.nlm.nih.gov/21245100/	yes
CYPs 28	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/28326839/	yes
P-gp 1626	inhibitor 3240 Sources: https://pubmed.ncbi.nlm.nih.gov/29979729/	yes

Drug as victim

Target	Modality	Activity
CYPs 33	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/16583304/	no
OATP1B1 403	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/16583304/	no
OATP1B3 347	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/16583304/	no
UGTs 13	substrate 3326 Sources: https://pubmed.ncbi.nlm.nih.gov/16583304/	no

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1632	inhibitor 1613 Sources: https://pubmed.ncbi.nlm.nih.gov/21742496/ \| https://pubmed.ncbi.nlm.nih.gov/21650221/

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P002KUN	https://www.1pchem.com/search?query=1P002KUN
A2B Chem	AB19535	http://a2bchem.com/prod/AB19535
AChemBlock	M15388	http://www.achemblock.com/catalogsearch/result/?q=M15388
AK Scientific	V2451	https://aksci.com/item_detail.php?cat=V2451
AOBIOUS INC	AOB2570	http://aobious.com/aobious/search?search_query=AOB2570
Achemo Scientific Limited	AC-66533	http://www.achemo.com/search/?Keyword=AC-66533
Ambeed	A122285	http://www.ambeed.com/search/Search.html?keyword=A122285
ApexBio Technology	A8171	https://www.apexbt.com/catalogsearch/result/?q=A8171
AstaTech	41168	http://astatechinc.com/CPSResult.php?CRNO=41168
Axon MedChem	1803	https://www.axonmedchem.com/product/1803
BOC Sciences	209783-80-2	http://www.bocsci.com/description.asp?cas=209783-80-2
BioSynth	W-201831	https://www.biosynth.com/en/products/life-science/other-biochemicals/products/W-201831
Capot Chemical	24433	https://www.capotchem.com/search.do?q=24433
Cayman Chemical	13284	http://www.caymanchem.com/app/template/Product.vm/catalog/13284
Chem Scene	CS-0511	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0511
ChemShuttle	140489	https://www.chemshuttle.com/catalogsearch/result/?q=140489
ChemShuttle	149125	https://www.chemshuttle.com/catalogsearch/result/?q=149125
Enamine	EN300-6488260	https://www.enaminestore.com/catalog/EN300-6488260
Excenen	EX-A038	http://www.excenen.com/searchresultlist.php?id=EX-A038
Exclusive Chemistry	2117	http://www.exchemistry.com/chem-catalog/product-2117.html
Fluorochem	50699	http://www.fluorochem.co.uk/Products/Product?code=050699
Hairui	ENJL011	http://www.hairuichem.com/en/product/search.do?q=ENJL011
KeyOrganics	AS-17906	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-17906
Lab Network	LN01285798	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01285798
MedChem Express	HY-12163	https://www.medchemexpress.com/search.html?q=HY-12163&ft=&fa=&fp=
MolPort	MolPort-005-942-713	https://www.molport.com/shop/molecule-link/MolPort-005-942-713
Molnova	M13310	https://www.molnova.com/en/serch-list.html?keywords=M13310
MuseChem	I002611	https://www.musechem.com/product/I002611.html
PI Chemicals	PI-38652	http://www.pipharm.com/catalog_products/PI-38652.html
Selleck Chemicals	S1053	http://www.selleckchem.com/search.html?searchDTO.searchParam=S1053
ShangHai Biochempartner	BCP000127	http://www.biochempartner.com/search_BCP000127
ShangHai Biochempartner	BCP01824	http://www.biochempartner.com/search_BCP01824
TargetMol	T6233	https://www.targetmol.com/search?keyword=T6233
Toronto Research Chemicals	E559300	https://www.trc-canada.com/product-detail/?CatNum=E559300
W&J PharmaChem	RT-	http://wjpharmachem.com/new/searcht.php?keyword=RT-
eMolecules	222573108	https://orderbb.emolecules.com/search/#?query=222573108
eMolecules	252359243	https://orderbb.emolecules.com/search/#?query=252359243
eMolecules	31239709	https://orderbb.emolecules.com/search/#?query=31239709
eNovation Chemicals	D395222	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D395222&searchbtn.x=0&searchbtn.y=0
eNovation Chemicals	D586663	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D586663&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-6200347297	https://mcule.com/MCULE-6200347297/
mcule	MCULE-9534048478	https://mcule.com/MCULE-9534048478/

PubMed

Title	Date	PubMed
The histone deacetylase inhibitor MS-275 interacts synergistically with fludarabine to induce apoptosis in human leukemia cells.	2004 Apr 1	15059916
Histone deacetylase inhibitors FK228, N-(2-aminophenyl)-4-[N-(pyridin-3-yl-methoxycarbonyl)amino- methyl]benzamide and m-carboxycinnamic acid bis-hydroxamide augment radiation-induced cell death in gastrointestinal adenocarcinoma cells.	2004 Jun 10	15069698
Determination of MS-275, a novel histone deacetylase inhibitor, in human plasma by liquid chromatography-electrospray mass spectrometry.	2004 May 25	15081922
Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-kappaB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation.	2005 Jul	15964800
In vivo imaging of retinoic acid receptor beta2 transcriptional activation by the histone deacetylase inhibitor MS-275 in retinoid-resistant prostate cancer cells.	2005 Jun 15	15651062
Histone deacetylase inhibitors and cancer: from cell biology to the clinic.	2005 Mar	15819394
Epigenetic modulation of retinoic acid receptor beta2 by the histone deacetylase inhibitor MS-275 in human renal cell carcinoma.	2005 May 1	15867257
Ex vivo therapy of malignant melanomas transplanted into organotypic brain slice cultures using inhibitors of histone deacetylases.	2006 Aug	16773328
Histone deacetylase inhibitors in cancer therapy.	2006 Aug-Sep	16939962
Curcumin is an inhibitor of p300 histone acetylatransferase.	2006 Mar	16787365
Anticancer activity of MS-275, a novel histone deacetylase inhibitor, against human endometrial cancer cells.	2006 Mar-Apr	16619490
Experimental therapy of malignant gliomas using the inhibitor of histone deacetylase MS-275.	2006 May	16731757
HDAC inhibitors induce apoptosis in glucocorticoid-resistant acute lymphatic leukemia cells despite a switch from the extrinsic to the intrinsic death pathway.	2007	17499001
Relationship between embryonic histonic hyperacetylation and axial skeletal defects in mouse exposed to the three HDAC inhibitors apicidin, MS-275, and sodium butyrate.	2007 Aug	17517827
Antitumor activity of the histone deacetylase inhibitor MS-275 in prostate cancer models.	2007 Aug 1	17520666
Measuring cytotoxicity: a new perspective on LC50.	2007 Jan-Feb	17352213
Histone deacetylase inhibitors affect dendritic cell differentiation and immunogenicity.	2007 Jul 1	17606727
Histone deacetylase inhibitors induce cell death and enhance the apoptosis-inducing activity of TRAIL in Ewing's sarcoma cells.	2007 Nov	17486365
Antiproliferative activities of a library of hybrids between indanones and HDAC inhibitor SAHA and MS-275 analogues.	2007 Nov 15	17897824
Histone deacetylase inhibitor MS-275 alone or combined with bortezomib or sorafenib exhibits strong antiproliferative action in human cholangiocarcinoma cells.	2007 Sep 7	17724801
Identification of ligand features essential for HDACs inhibitors by pharmacophore modeling.	2008 Apr	18061500
MS-275 synergistically enhances the growth inhibitory effects of RAMBA VN/66-1 in hormone-insensitive PC-3 prostate cancer cells and tumours.	2008 Apr 8	18349838
Sp1-mediated TRAIL induction in chemosensitization.	2008 Aug 15	18701496
Defining the molecular action of HDAC inhibitors and synergism with androgen deprivation in ERG-positive prostate cancer.	2008 Dec 15	18798265
Regulation of arginase-1 expression in macrophages by a protein kinase A type I and histone deacetylase dependent pathway.	2008 Feb 1	17577214
Inhibition of MEK/ERK signaling synergistically potentiates histone deacetylase inhibitor-induced growth arrest, apoptosis and acetylation of histone H3 on p21waf1 promoter in acute myelogenous leukemia cell.	2008 Jul	18185526
p21(WAF1/CIP1) induction by 5-azacytosine nucleosides requires DNA damage.	2008 Jun 5	18223691
Probing the elusive catalytic activity of vertebrate class IIa histone deacetylases.	2008 Mar 15	18308563
Improved synthesis of histone deacetylase inhibitors (HDIs) (MS-275 and CI-994) and inhibitory effects of HDIs alone or in combination with RAMBAs or retinoids on growth of human LNCaP prostate cancer cells and tumor xenografts.	2008 Mar 15	18166465
MS-275, a novel histone deacetylase inhibitor with selectivity against HDAC1, induces degradation of FLT3 via inhibition of chaperone function of heat shock protein 90 in AML cells.	2008 Sep	18394702
Induction of Foxp3+ regulatory T cells with histone deacetylase inhibitors.	2009	19358983
[Effects of histone deacetylase inhibitor MS-275 on expression of survivin and NF-kappaB in the human myeloma cell line U266 cells].	2009 Apr	19615275
Reactivation of death receptor 4 (DR4) expression sensitizes medulloblastoma cell lines to TRAIL.	2009 Jul	19148581
Epigenetic modifiers: basic understanding and clinical development.	2009 Jun 15	19509169
"Shock and kill" effects of class I-selective histone deacetylase inhibitors in combination with the glutathione synthesis inhibitor buthionine sulfoximine in cell line models for HIV-1 quiescence.	2009 Jun 2	19486542
Inhibitors of poly ADP-ribose polymerase (PARP) induce apoptosis of myeloid leukemic cells: potential for therapy of myeloid leukemia and myelodysplastic syndromes.	2009 May	19407318
Three epigenetic drugs up-regulate homeobox gene Rhox5 in cancer cells through overlapping and distinct molecular mechanisms.	2009 Nov	19679824
HDAC inhibitor SNDX-275 induces apoptosis in erbB2-overexpressing breast cancer cells via down-regulation of erbB3 expression.	2009 Nov 1	19826038
Efficacy of MS-275, a selective inhibitor of class I histone deacetylases, in human colon cancer models.	2009 Oct	19724929
Epigenetic influences on sensory regeneration: histone deacetylases regulate supporting cell proliferation in the avian utricle.	2009 Sep	19340485
Antidepressant actions of histone deacetylase inhibitors.	2009 Sep 16	19759294
Anti-leukemia activity of MS-275 histone deacetylase inhibitor implicates 4-1BBL/4-1BB immunomodulatory functions.	2009 Sep 17	19759901
HDAC inhibitors, MS275 and SBHA, enhances cytotoxicity induced by oxaliplatin in the colorectal cancer cell lines.	2009 Sep 18	19596269
Early epigenetic changes and DNA damage do not predict clinical response in an overlapping schedule of 5-azacytidine and entinostat in patients with myeloid malignancies.	2009 Sep 24	19546476
MS275 enhances cytotoxicity induced by 5-fluorouracil in the colorectal cancer cells.	2010 Feb 10	19853597
Histone deacetylase inhibitors induce thyroid cancer-specific apoptosis through proteasome-dependent inhibition of TRAIL degradation.	2010 Jan 7	19802013

Patents

Sample Use Guides

In Vivo Use Guide

Phase I trial data have shown that daily dosing of entinostat is not tolerated. Administration of the drug every 2 weeks or weekly at doses of ≤10 mg/m2 was much better tolerated than daily dosing. The recommended phase II dose for entinostat is 4 mg/ m2 once weekly (solid tumors).

Route of Administration: Oral

In Vitro Use Guide

Entinostat (MS-275) exerts dose-dependent effects in human leukemia cells, i.e., p21(CIP1/WAF1)-dependent growth arrest and differentiation at low drug concentrations (e.g., 1 uM) and a marked induction of ROS, mitochondrial damage, caspase activation, and apoptosis at higher concentrations (e.g., 5 uM).

Substance Class	Chemical Created by `admin` on `Wed Jul 05 23:27:03 UTC 2023` Edited by `admin` on `Wed Jul 05 23:27:03 UTC 2023`
Record UNII	1ZNY4FKK9H
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

ENTINOSTAT

Official Name

English

Entinostat [WHO-DD]

Common Name

English

ENTINOSTAT [USAN]

Common Name

English

MS-27-275

Code

English

Pyridin-3-ylmethyl ({4-[(2-aminophenyl)carbamoyl]phenyl}methyl)carbamate

Systematic Name

English

CARBAMIC ACID, N-((4-(((2-AMINOPHENYL)AMINO)CARBONYL)PHENYL)METHYL)-, 3- PYRIDINYLMETHYL ESTER

Common Name

English

entinostat [INN]

Common Name

English

MS-275-27

Code

English

ENTINOSTAT [JAN]

Common Name

English

SNDX-275

Code

English

Classification Tree Code System Code

EU-Orphan Drug

EU/3/10/732